A fibroblast-dependent TGF-beta1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.

Fibrosis, a condition where tissue becomes thickened and scarred, is a significant issue in lung diseases like Interstitial Lung Disease (ILD). In healthy lungs, there is a delicate balance between different cell types—especially alveolar fibroblasts and epithelial cells . This balance is crucial for maintaining lung health, repairing injuries, and preventing excessive scarring (fibrosis). However, the mechanisms that regulate these interactions are not well understood. To explore this further, researchers focused on a specific signaling pathway in fibroblasts triggered by a protein called TGFβ1. This pathway is known to drive fibrosis. A compound called epigallocatechin gallate (EGCG), a natural substance found in green tea, was used to block TGFβ1 signaling selectively in fibroblasts. EGCG was administered to ILD patients undergoing diagnostic lung biopsies. Spare tissue from these biopsies was analyzed using advanced single-cell RNA sequencing, a technology that provides a detailed view of gene activity in individual cells. The results revealed that in untreated patients, fibroblasts showed elevated TGFβ1 signaling compared to non-diseased lung tissues or lungs from patients with end-stage ILD. Importantly, EGCG treatment reduced TGFβ1 signaling in fibroblasts, along with several inflammation-related and stress-related pathways. This suggests that EGCG could help dampen the processes driving lung fibrosis. One surprising finding was the discovery of a previously unrecognized target of TGFβ1 signaling in fibroblasts: a protein called secreted frizzle-like receptor protein 2 (sFRP2). This protein was found to be produced near specific epithelial cells called type II alveolar epithelial cells (AEC2s). These cells are critical for repairing lung damage and maintaining the structure of the air sacs. Further experiments using laboratory models, including organoids (miniature lung-like structures grown from cells) and lung tissue slices, revealed more details about this process. TGFβ1 signaling caused AEC2s to enter an unusual state characterized by the presence of a protein called KRT17. This state set the stage for sFRP2 to trigger a transition in AEC2s to another cell type, known as KRT5+ basal cells. These basal cells are more mature but may not function properly in the context of lung repair. The researchers also identified a critical role for the Wnt signaling pathway in this process. Specifically, sFRP2 interacts with a Wnt receptor called Frizzled 5 , activating a cascade of events involving calcineurin signaling. This ultimately led to the accumulation of a protein called NFATc3 in the cell nucleus and the activation of KRT5. These findings shed light on the step-by-step molecular changes that drive fibrosis in ILD. They highlight how abnormal TGFβ1 signaling can disrupt the communication between fibroblasts and epithelial cells, leading to dysfunctional lung repair. Importantly, the study demonstrates the potential of EGCG as a therapeutic approach to counteract these harmful changes and reduce fibrosis-related gene activity. By uncovering the link between TGFβ1 signaling and non-canonical Wnt pathways through sFRP2, the research also opens up new avenues for understanding and potentially treating lung diseases like Idiopathic Pulmonary Fibrosis.